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Exploring the Plasmatic Platelet-Activating Factor Acetylhydrolase Activity in Patients with Anti-Phospholipid Antibodies

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Exploring the Plasmatic Platelet-Activating Factor Acetylhydrolase Activity in Patients with Anti-Phospholipid Antibodies Autoimmun Highlights (2017) 8:5 https://doi.org/10.1007/s13317-017-0092-7 ORIGINAL ARTICLE Exploring the plasmatic platelet-activating factor acetylhydrolase activity in patients with anti-phospholipid antibodies 1,2 1 1 2 Martina Fabris • Adriana Cifu` • Cinzia Pistis • Massimo Siega-Ducaton • 1 1,2 3 1,2 Desre` Ethel Fontana • Roberta Giacomello • Elio Tonutti • Francesco Curcio Received: 23 December 2016 / Accepted: 12 March 2017 / Published online: 25 March 2017 Ó The Author(s) 2017. This article is an open access publication Abstract Conclusions PAF-AH plasmatic activity is particularly up- Purpose To explore the role of plasmatic platelet-activat- regulated in LAC? and in ab2GPI IgG? patients, possibly ing factor acetylhydrolase (PAF-AH), a marker of cardio- representing an alternative prognostic biomarker for the vascular risk, in patients with anti-phospholipid antibodies therapeutic management of APS patients. (aPL). Methods PAF-AH activity was assessed in a series of 167 Keywords Platelet-activating factor acetylhydrolase Á unselected patients screened for aPL in a context of Anti-phospholipid syndrome Á Anti-beta2-glycoprotein I thrombotic events, risk of thrombosis or obstetric compli- antibodies Á Anti-prothrombin/phosphatidylserine cations and in 77 blood donors. antibodies Á Lupus anticoagulant Á Atherosclerosis Results 116/167 patients showed positive results for at least one aPL among IgG/IgM anti-prothrombin/phos- phatidylserine (aPS/PT), anti-cardiolipin (aCL), anti-beta2- Introduction glycoprotein I (ab2GPI) or lupus anticoagulant (LAC), while 51/167 patients resulted aPL-negative. LAC? Anti-phospholipid syndrome (APS) is a hypercoagulable patients disclosed higher PAF-AH than LAC-negative disorder clinically displayed by venous or arterial throm- (22.1 ± 6.4 nmol/min/ml vs. 19.5 ± 4.1 nmol/min/ml; bosis and/or adverse obstetric events, accompanied by p = 0.0032), and aPL-negative patients (p = 0.03). persistent and elevated levels of anti-phospholipid anti- Patients presenting positive IgG ab2GPI disclosed higher bodies (aPL) [1]. According to the 2006 revised interna- PAF-AH than patients with only IgM ab2GPI-positive tional classification criteria [2], patients with definite antibodies (23.1 ± 7.2 nmol/min/ml vs. 20.1 ± 5.3 nmol/ diagnosis of APS are those presenting positive lupus anti- min/ml; p = 0.035), as well as than patients showing only coagulant (LAC) and/or one among anti-cardiolipin (aCL) isolated LAC, aCL or aPS/PT (16.9 ± 3.8 nmol/min/ml; IgG or IgM or anti-beta2 glycoprotein I (ab2GPI) IgG or p = 0.003). IgM antibodies. However, during the last international congress on aPL antibodies, the major experts defined the role of other so-called ‘‘non criteria’’ antibodies, con- & Martina Fabris [email protected] tributing to assess the risk of thrombosis or the identifica- tion of potential seronegative APS, such as the anti- 1 Department of Medical and Biological Sciences, University prothrombin/phosphatidylserine antibodies (aPS/PT) [3]. of Udine, Padiglione CSL - Via Chiusaforte, Ingresso F3, Of note, the combination of ab2GPI, aPS/PT and LAC has 33100 Udine, Italy 2 demonstrated the best diagnostic accuracy for APS [4] and Institute of Clinical Pathology, Department of Laboratory aPS/PT were recently recommended as a surrogate for Medicine, University Hospital of Udine, Padiglione CSL - Via Chiusaforte, Ingresso F3, 33100 Udine, Italy LAC when specific inhibitors and/or analytical variables may affect its interpretation [5]. However, no definite 3 Laboratory of Immunopathology and Allergy, Department of Laboratory Medicine, University Hospital of Udine, Udine, recommendations are available to guide the therapeutic Italy approach in patients positive only for aPS/PT antibodies. 123 5 Page 2 of 6 Autoimmun Highlights (2017) 8:5 Platelet-activating factor acetylhydrolase (PAF-AH) is a Methods family of enzymes, the most abundant of which is the plasma form, also called lipoprotein-associated phospho- The plasmatic PAF-AH activity was assessed by a colori- lipase A2 (Lp-PLA2) [6]. The plasmatic PAF-AH is con- metric assay (PAF-AH Assay Kit-Cayman Chemical stitutively active and circulates bound to LDL, HDL and Company, Ann Arbor, MI, USA). Briefly, plasma or serum other lipoproteins and catalyses the hydrolysis of the sn2 samples were incubated with the 2-thio PAF substrate, i.e., acetate of PAF and PAF mimetics, which are early medi- hydrolyzed by PAF-AH at the sn2-position releasing free ators of inflammation [7]. PAF activates a variety of cells thiols detected by DTNB Ellman’s reagent (5,50-dithio-bis- of the innate immune system promoting migration, adhe- 2-nitrobenzoic acid). sion and inflammatory effects. Thus, PAF-AH while Anti-cardiolipin (aCL) and anti-beta2 glycoprotein I inactivating PAF is considered an important factor in pre- (ab2GPI) IgG/IgM antibodies were investigated in all venting an exaggerated inflammatory response and in patients, while 125 patients were tested for lupus antico- protecting cells from uncontrolled oxidative damage [8]. agulant and 125 for anti-phosphatidylserine/prothrombin Several studies reported a significant association (aPS/PT) IgG/IgM antibodies. aCL and ab2GpI antibodies between higher PAF-AH plasmatic activity and the sever- were analysed by chemiluminescence (Zenit RA instru- ity of cardiovascular (CV) disease and identified PAF-AH ment by A. Menarini Diagnostics, Italy), while aPS/PT as a marker of vascular inflammation and atherosclerotic were assayed by Quanta Lite aPS/PT IgG/IgM ELISA kit plaque instability [9–11]. (Inova Diagnostics Inc, San Diego, CA). Plasma samples More and more papers in recent literature emphasize the were tested for the presence of LAC according to the relevant link between endothelial dysfunction, atheroscle- recommended criteria from the ISTH Subcommittee on rosis and APS [12–14]. Chronic inflammation is involved Lupus Anticoagulant-Phospholipid-dependent antibodies in various stages of development of the atherosclerotic and optimized according to recently published standard- plaques. Among the key molecules involved in the ization [17, 18]. Total cholesterol, low-density lipoproteins atherosclerotic process are heat-shock proteins, oxidized (LDL), high-density lipoproteins (HDL) and triglycerides LDL (oxLDL) and b2GPI. The latter is identified as an were analysed by diagnostic methods. anti-atherogenic agent involved in the atheromatous plaque formation in APS patients, since it is targeted by the Statistic analyses ab2GPI antibodies, typically associated with APS [15, 16]. In this study we analysed PAF-AH plasmatic activity in Quantitative variables were expressed as mean ± standard a large series of unselected patients screened for aPL deviation and checked for normality distribution by the antibodies in a reference laboratory for the diagnosis of Shapiro–Wilk test. Statistical analyses were performed autoimmune diseases, investigating its association with with GraphPad Prism software. To compare biomarker different pattern of aPL positivity. serum levels between patients and controls, either Mann– Whitney or unpaired t test was used when appropriate. Correlation analyses were performed using the Pearson’s or Materials and methods the Spearman’s rank correlation coefficient. Patients Results The study was conducted in 167 consecutive unselected patients (124 females and 69 males; mean age: PAF-AH plasmatic activity in patients and controls: 51 ± 16 years) who were screened for the presence of aPL correlation with lipid metabolic markers at the Laboratory of Immunopathology of the University Hospital of Udine in the context of routine testing for PAF-AH plasmatic activity in BDs disclosed a mean value thrombotic events, risk of thrombosis or obstetric compli- of 15.6 ± 4 nmol/min/ml (range 5.9–28.4). As expected cations. Patients were compared to 77 blood donors (BDs; [11], a significant correlation was found between PAF-AH 39 females and 38 males; mean age: 39 ± 13 years) and total cholesterol (r = 0.25; p = 0.032), a stronger enrolled at the Transfusion Unit of the same Hospital. All direct correlation with LDL (r = 0.46, p \ 0.0001) and a patients and controls gave their informed consent to the highly significant inverse correlation with HDL study according to the Declaration of Helsinki (1964) and (r =-0.45, p \ 0.0001). No correlation was found with to the Italian legislation (Authorization of the Privacy age and sex (15.5 ± 5 nmol/min/ml in females vs. Guarantor No. 9, 12th of December 2013). 15.7 ± 3.3 nmol/min/ml in males). 123 Autoimmun Highlights (2017) 8:5 Page 3 of 6 5 Of the 167 patients undergoing aPL investigation, 116 than LAC-negative patients (22.1 ± 6.4 nmol/min/ml vs. showed at least one positive aPL among LAC, aCL, ab2GPI 19.5 ± 4.1 nmol/min/ml; p = 0.0032). Of note, total or aPS/PT antibodies, while 51 resulted all negative. PAF- cholesterol levels did not differ between LAC? and LAC- AH plasmatic activity was markedly more elevated in the negative patients (202 ± 39 mg/dl vs. 201 ± 34 mg/dl; overall patients (19.8 ± 5.5 nmol/min/ml) than in BDs p = ns), as well as LDL (113 ± 39 mg/dl vs. (p \ 0.0001), but no difference was found between aPL? 108 ± 26 mg/dl; p = ns) and HDL serum levels and aPL-negative patients (19.9 ± 5.8 nmol/min/ml vs. (60 ± 21 mg/dl vs. 63 ± 21 mg/dl; p = ns). Moreover, 19.6 ± 4.7 nmol/min/ml; Fig. 1). LAC? patients disclosed higher PAF-AH than aPL-nega- Of note, total cholesterol levels did not differ signifi- tive patients (p = 0.03), with again no difference with cantly between BDs and the overall patients, nor between regard to HDL (62 ± 24 mg/dl in aPL-negative; p = ns) BDs and aPL? patients (188 ± 38 mg/dl vs. and LDL (127 ± 42 mg/dl in aPL-negative; p = ns). As 198 ± 42 mg/dl; p = 0.10) and between aPL? and aPL- illustrated in Fig. 2, patients presenting ab2GPI IgG? negative patients (206 ± 52 mg/dl; p = 0.47).
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